The failure or modest success of previous vaccine approaches to protect from HIV-1 infection have highlighted that our understanding of protective immunity in HIV-1 infection is very limited, and that novel, innovative strategies are needed to overcome the tremendous challenges we are facing in HIV-1 vaccine design. NK cells represent important early effector cells against viral infections, and increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans. While the ability of NK cells to eliminate infected cells has long been recognized, recent studies conducted in mouse models revealed a subset of murine NK cells that can acquire specific long-lived memory of multiple haptens and viral antigens, including HIV-1 antigens. These exciting data suggest that a subset of NK cells in humans may also mediate immunological memory responses to pathogens in humans, and that NK cell responses may significantly contribute to the protective effect mediated by HIV-1 vaccines. Therefore, we propose to comprehensively explore HIV-1-specific NK cell responses in HIV-1-infected subjects and in HIV-1-negative individuals following immunization with HIV-1 vaccines, including vaccines that are currently being tested in humans. The results of these innovative explorative studies could provide the rationale to harness antigen-specific NK cell responses to enhance the potency of HIV-1 vaccines and to improve the design of vaccines to prevent other infectious diseases for which there is currently no available or effective enough prophylaxis.